Hox genes were first discovered in fruit flies and recognized to be very important for proper segmentation of the insect and placement of body parts. It was discovered soon afterwards that members of this gene family in fruit flies were present in the genomes of all mammals and vertebrates. The importance of these findings resulted in the 1995 Nobel Prize in physiology and medicine shared by three investigators for their discoveries concerning the "genetic control of early embryonic development": http://nobelprize.org/medicine/laureates/1995/press.html

HOX genes are found in four paralogous gene clusters (A, B, C, D) in humans, each on a different chromosome and each containing up to 11 genes. The order of HOX genes within each cluster corresponds to their temporal and spatial expression patterns during development. Generally, genes at the 3' ends of each cluster are expressed early in anterior regions (head) of the human embryo, whereas genes at the 5' ends of each cluster are expressed later in posterior regions (hands and feet). This is known as the colinearity principle of HOX gene expression.

HOXA1 is the most 3' HOX gene in cluster "A" and the first HOX gene expressed in mammals. It is also among the first genes expressed in the central nervous system, and accordingly, plays a critical role in brain and head development. HOXA1 is primarily responsible for segmenting the embryonic hindbrain into seven transient compartments called rhombomeres. Each rhombomere has a distinct set of molecular and cellular properties that is necessary for organizing groups of immature neurons into functional networks that will eventually mediate important functions such as breathing, eye movement, and mastication.

(A) Wild-type isoforms. Isoform 1 (top) contains a PBX binding domain in exon 1 and homeodomain in exon 2, which are critical for transcriptional activity. Alternatively spliced isoform 2 (middle) lacks the PBX domain and homeodomain, and contains 19 alternative C-terminal amino acids. Isoform 3 (bottom) results from absent splicing, and contains exon 1 followed by 9 alternative C-terminal amino acids. Isoforms 2 and 3 have no known function. (B) The Saudi 175-176insG frame-shift mutation is predicted to result in a mutant protein composed of the normal first 58 N-terminal amino acid residues followed by 118 altered residues in isoforms 1 (top) and 3 (bottom), and 81 altered residues in isoform 2 (middle). The Turkish 84C>G nonsense mutation (C) and the Athabascan 76C>T nonsense mutation (D) are predicted to truncate all three isoforms at amino acid residues 28 (Y28X) and 26 (R26X), respectively. All mutant proteins lack known functional domains.

Below is a diagram describing the proposed pathology of the horizontal gaze abnormalities in the HOXA1 related syndromes. Loss of HOXA1 function results in bilateral absence of the abducens cranial nerve (green hash marks), which normally innervates the lateral rectus muscle. Contraction of this muscle results in eye movement away from the nose (abduction).